IMMR
Mechanisms of Mismatch repair inactivation and identification of genes suppressing mutations
| Coordinatore | DEUTSCHES KREBSFORSCHUNGSZENTRUM
Organization address
address: Im Neuenheimer Feld 280 contact info |
| Nazionalità Coordinatore | Germany [DE] |
| Totale costo | 100˙000 € |
| EC contributo | 100˙000 € |
| Programma | FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) |
| Code Call | FP7-PEOPLE-2013-CIG |
| Funding Scheme | MC-CIG |
| Anno di inizio | 2014 |
| Periodo (anno-mese-giorno) | 2014-04-01 - 2018-03-31 |
Partecipanti
| # | ||||
|---|---|---|---|---|
| 1 |
DEUTSCHES KREBSFORSCHUNGSZENTRUM
Organization address
address: Im Neuenheimer Feld 280 contact info |
DE (HEIDELBERG) | coordinator | 100˙000.00 |
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Obiettivo del progetto (Objective)
'The fidelity of DNA replication, and therefore the stability of the genome, relies on the DNA Mismatch repair (MMR) pathway, which recognizes DNA replication errors and promotes repair by an excision and re-synthesis mechanism. Mutations that inactivate MMR are associated to Lynch Syndrome, an early-onset cancer disorder characterized by accumulation of mutations at repetitive sequences or microsatellite instability (MSI). Interestingly, a significant number of tumors with MSI have not been correlated with MMR defects, suggesting that additional factors may influence MMR proficiency or DNA replication fidelity The current proposal aims to investigate alternative molecular mechanisms that result in MMR inactivation and to identify unrecognized genes that are essential for suppression of mutations. We will characterize a subset of Msh6 dominant mutations that abolishes MMR function by inactivating the partially redundant Msh2-Msh3 pathway. Furthermore, we will carry out a genetic screen to identify dominant mutations on the MMR-related genes: MSH3, MLH2 and MLH3 that result in MMR inactivation. Finally, we will carry out a genome-wide screen in budding yeast, to identify mutants that results in increased mutation rates. The human homologs of the identified yeast genes will be further characterized in human cell lines by knock-down experiments and in vivo mutator assays. This proposal is directed to achieve a better understanding of mechanisms preventing accumulation of mutations and will provide relevant information for diagnosis of cancer susceptibility syndromes.'